Hydrops fetalis

disease

On this page

Also known as familial non-immune hydrops fetalisfetal anasarcafetal edemafetal hydropsfoetal anasarcafoetal hydropsfoetal oedemageneralised foetal oedemageneralized fetal edemaHFhydrops fetalis (disease)hydrops fetalis nonimmuneidiopathic hydrops fetalis

Summary

Hydrops fetalis (MONDO:0015193) is a disease caused by variants in FZD6 and MYBBP1A, with 17 cohort genes and 6 clinical trials.

At a glance

Prevalence: >1 / 1000 (Ireland) [Orphanet-validated]
Causal genes: FZD6 (GenCC Strong), MYBBP1A (GenCC Strong)
Cohort genes: 17
ClinVar variants: 24
Phenotypes (HPO): 24
Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	>1 / 1000	134	Ireland	Validated
Prevalence at birth	>1 / 1000	380	Turkey	Validated
Prevalence at birth	>1 / 1000	180	Thailand	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0000464	Abnormality of the neck	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0001541	Ascites	Frequent (30-79%)
HP:0001790	Nonimmune hydrops fetalis	Frequent (30-79%)
HP:0005268	Spontaneous abortion	Frequent (30-79%)
HP:0030005	Capillary leak	Frequent (30-79%)
HP:0032548	Increased placental thickness	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0001004	Lymphedema	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0001698	Pericardial effusion	Occasional (5-29%)
HP:0001871	Abnormality of blood and blood-forming tissues	Occasional (5-29%)
HP:0002202	Pleural effusion	Occasional (5-29%)
HP:0007430	Generalized edema	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)
HP:0032169	Severe infection	Occasional (5-29%)
HP:0000079	Abnormality of the urinary system	Very rare (<1-4%)
HP:0001627	Abnormal heart morphology	Very rare (<1-4%)
HP:0002652	Skeletal dysplasia	Very rare (<1-4%)
HP:0002664	Neoplasm	Very rare (<1-4%)
HP:0011024	Abnormality of the gastrointestinal tract	Very rare (<1-4%)
HP:0011675	Arrhythmia	Very rare (<1-4%)
HP:0031110	Twin-to-twin transfusion	Very rare (<1-4%)
HP:0100763	Abnormality of the lymphatic system	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hydrops fetalis
Mondo ID	MONDO:0015193
MeSH	D015160
Orphanet	1041
NCIT	C84767
SNOMED CT	276508000
UMLS	C0020305
MedGen	6947
GARD	0002783
MedDRA	10020529
Is cancer (heuristic)	no

Also known as: familial non-immune hydrops fetalis · fetal anasarca · fetal edema · fetal hydrops · foetal anasarca · foetal hydrops · foetal oedema · generalised foetal oedema · generalized fetal edema · HF · hydrops fetalis · hydrops fetalis (disease) · hydrops fetalis nonimmune · idiopathic hydrops fetalis

Data availability: 24 ClinVar variants · 4 GenCC gene-disease records · 1 HPO phenotype · 4 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › hydrops fetalis

Subtypes (2): non-immune hydrops fetalis, immune hydrops fetalis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

24 retrieved; paginated sample, class counts are floors:

7 pathogenic, 6 uncertain significance, 5 likely pathogenic, 4 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11407	NM_014009.4(FOXP3):c.1189C>T (p.Arg397Trp)	FOXP3	Pathogenic	criteria provided, multiple submitters, no conflicts
978651	NM_001142864.4(PIEZO1):c.1536_1537del (p.Cys513fs)	HSALR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9993	NM_001278116.2(L1CAM):c.3581C>T (p.Ser1194Leu)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430474	NM_005055.5(RAPSN):c.149_153delinsAGATGGGCCGCTACAAGGAGATGG (p.Val50fs)	RAPSN	Pathogenic	criteria provided, multiple submitters, no conflicts
978660	NM_005055.5(RAPSN):c.1146C>A (p.Cys382Ter)	RAPSN	Pathogenic	criteria provided, single submitter
1342869	NM_001036.6(RYR3):c.6248A>C (p.Gln2083Pro)	RYR3	Pathogenic	criteria provided, single submitter
55994	NM_000111.3(SLC26A3):c.269_270dup (p.Gly91fs)	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
978616	NM_000111.3(SLC26A3):c.2006C>A (p.Ser669Ter)	SLC26A3	Pathogenic	criteria provided, single submitter
978618	NM_000111.3(SLC26A3):c.1000G>T (p.Glu334Ter)	SLC26A3	Pathogenic	criteria provided, single submitter
978636	NM_014009.4(FOXP3):c.1117TTC[1] (p.Phe374del)	FOXP3	Likely pathogenic	criteria provided, single submitter
978652	NM_001142864.4(PIEZO1):c.4610_4617dup (p.Ser1540delinsAlaProTer)	PIEZO1	Likely pathogenic	criteria provided, single submitter
978662	NM_000540.3(RYR1):c.2286del (p.Val763fs)	RYR1	Likely pathogenic	criteria provided, single submitter
976212	NM_022902.5(SLC30A5):c.832_836del (p.Ile278fs)	SLC30A5	Likely pathogenic	criteria provided, single submitter
988899	NM_022902.5(SLC30A5):c.1981_1982del (p.His661fs)	SLC30A5	Likely pathogenic	criteria provided, single submitter
978649	NM_001142864.4(PIEZO1):c.3340C>G (p.Gln1114Glu)	PIEZO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
978650	NM_001142864.4(PIEZO1):c.7184C>T (p.Ala2395Val)	PIEZO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
978654	NM_001142864.4(PIEZO1):c.4885G>A (p.Gly1629Arg)	PIEZO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
159856	NM_000540.3(RYR1):c.6721C>T (p.Arg2241Ter)	RYR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
978661	NM_002890.3(RASA1):c.1900C>T (p.Gln634Ter)	CCNH	Uncertain significance	criteria provided, single submitter
978631	NM_000079.4(CHRNA1):c.119G>A (p.Arg40Gln)	CHRNA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
523310	GRCh37/hg19 14q24.3(chr14:76105695-76107636)	FLVCR2	Uncertain significance	criteria provided, single submitter
634993	NM_078471.4(MYO18A):c.2932G>A (p.Ala978Thr)	MYO18A	Uncertain significance	criteria provided, single submitter
2692226	NM_001142864.4(PIEZO1):c.6392T>C (p.Leu2131Pro)	PIEZO1	Uncertain significance	no assertion criteria provided
978653	NM_001142864.4(PIEZO1):c.4519G>C (p.Val1507Leu)	PIEZO1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 28 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FZD6	Strong	Autosomal recessive	hydrops fetalis	3
MYBBP1A	Strong	Autosomal recessive	hydrops fetalis
CELSR1	Limited	Autosomal dominant	hydrops fetalis	6
SERPINA11	Limited	Autosomal recessive	hydrops fetalis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CELSR1	Orphanet:569816	CELSR1-related late-onset primary lymphedema
FZD6	Orphanet:280654	Autosomal recessive nail dysplasia
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
CHRNA1	Orphanet:33108	Lethal multiple pterygium syndrome
CHRNA1	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
FLVCR2	Orphanet:221126	Fowler vasculopathy
PIEZO1	Orphanet:3202	Dehydrated hereditary stomatocytosis
PIEZO1	Orphanet:568062	PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis
SLC26A3	Orphanet:53689	Congenital chloride diarrhea
FOXP3	Orphanet:37042	Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
L1CAM	Orphanet:1497	X-linked complicated corpus callosum dysgenesis
L1CAM	Orphanet:2182	Hydrocephalus with stenosis of the aqueduct of Sylvius
L1CAM	Orphanet:2466	MASA syndrome
L1CAM	Orphanet:306617	X-linked complicated spastic paraplegia type 1
RAPSN	Orphanet:33108	Lethal multiple pterygium syndrome
RAPSN	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
RAPSN	Orphanet:994	Fetal akinesia deformation sequence

Cohort genes → proteins

17 cohort genes, 16 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CELSR1	HGNC:1850	ENSG00000075275	Q9NYQ6	Cadherin EGF LAG seven-pass G-type receptor 1	gencc
SERPINA11	HGNC:19193	ENSG00000186910	Q86U17	Serpin A11	gencc
FZD6	HGNC:4044	ENSG00000164930	O60353	Frizzled-6	gencc
MYBBP1A	HGNC:7546	ENSG00000132382	Q9BQG0	Myb-binding protein 1A	gencc
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
RYR3	HGNC:10485	ENSG00000198838	Q15413	Ryanodine receptor 3	clinvar
CCNH	HGNC:1594	ENSG00000134480	P51946	Cyclin-H	clinvar
SLC30A5	HGNC:19089	ENSG00000145740	Q8TAD4	Proton-coupled zinc antiporter SLC30A5	clinvar
CHRNA1	HGNC:1955	ENSG00000138435	P02708	Acetylcholine receptor subunit alpha	clinvar
FLVCR2	HGNC:20105	ENSG00000119686	Q9UPI3	Choline/ethanolamine transporter FLVCR2	clinvar
PIEZO1	HGNC:28993	ENSG00000103335	Q92508	Piezo-type mechanosensitive ion channel component 1	clinvar
SLC26A3	HGNC:3018	ENSG00000091138	P40879	Chloride anion exchanger	clinvar
MYO18A	HGNC:31104	ENSG00000196535	O95411	Putative TGFB1-induced anti-apoptotic factor 1	clinvar
HSALR1	HGNC:56095	ENSG00000224888		HSP90AB1 associated lncRNA 1	clinvar
FOXP3	HGNC:6106	ENSG00000049768	Q9BZS1	Forkhead box protein P3	clinvar
L1CAM	HGNC:6470	ENSG00000198910	P32004	Neural cell adhesion molecule L1	clinvar
RAPSN	HGNC:9863	ENSG00000165917	Q13702	43 kDa receptor-associated protein of the synapse	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CELSR1	Cadherin EGF LAG seven-pass G-type receptor 1	Receptor that may have an important role in cell/cell signaling during nervous system formation.
FZD6	Frizzled-6	Receptor for Wnt proteins.
MYBBP1A	Myb-binding protein 1A	May activate or repress transcription via interactions with sequence specific DNA-binding proteins.
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
RYR3	Ryanodine receptor 3	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm in muscle and thereby plays a role in triggering muscle contraction.
CCNH	Cyclin-H	Regulates CDK7, the catalytic subunit of the CDK-activating kinase (CAK) enzymatic complex.
SLC30A5	Proton-coupled zinc antiporter SLC30A5	Together with SLC30A6 forms a functional proton-coupled zinc ion antiporter mediating zinc entry into the lumen of organelles along the secretory pathway.
CHRNA1	Acetylcholine receptor subunit alpha	Upon acetylcholine binding, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
FLVCR2	Choline/ethanolamine transporter FLVCR2	Choline uniporter that specifically mediates choline uptake at the blood-brain-barrier.
PIEZO1	Piezo-type mechanosensitive ion channel component 1	Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain.
SLC26A3	Chloride anion exchanger	Mediates chloride-bicarbonate exchange with a chloride bicarbonate stoichiometry of 2:1 in the intestinal epithelia.
MYO18A	Putative TGFB1-induced anti-apoptotic factor 1	Inhibits the cytotoxic effects of TNF and overexpressed TNF receptor adapters TRADD, FADD, and RIPK1.
FOXP3	Forkhead box protein P3	Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg).
L1CAM	Neural cell adhesion molecule L1	Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors.
RAPSN	43 kDa receptor-associated protein of the synapse	Postsynaptic protein required for clustering of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction.

Protein-family classification

Druggable: 8 · Difficult: 3 · Unknown: 6 · Druggable fraction: 0.47

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	2	13.1×	0.079
Transporter	2	9.2×	0.079
GPCR	2	2.8×	0.419
Antibody/Immunoglobulin	1	1.7×	0.849
Scaffold/PPI	1	1.0×	0.849
Transcription factor	2	1.0×	0.849
Enzyme (other)	1	0.7×	0.883
Other/Unknown	6	0.6×	0.974

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CELSR1	GPCR	yes		EGF-type_Asp/Asn_hydroxyl_site, GPS, EGF
SERPINA11	Other/Unknown	no		Serpin_fam, Serpin_dom, Serpin_sf
FZD6	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM
MYBBP1A	Enzyme (other)	yes	2.3.1.48	DNA_pol_V/MYBBP1A, ARM-like, ARM-type_fold
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
RYR3	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
CCNH	Other/Unknown	no		Cyclin_N, Cyclin-like_dom, CyclinH/Ccl1
SLC30A5	Other/Unknown	no		Cation_efflux, Cation_efflux_TMD_sf, Msc2-like
CHRNA1	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
FLVCR2	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
PIEZO1	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28
SLC26A3	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom
MYO18A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, PDZ, Myosin_head_motor_dom-like
HSALR1	Other/Unknown	no
FOXP3	Transcription factor	no		Fork_head_dom, Znf_C2H2_type, TF_fork_head_CS_2
L1CAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
RAPSN	Transcription factor	no		Postsynaptic, Znf_RING, TPR-like_helical_dom_sf

Expression context

Cohort genes with no expression data: 0.

15 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	4
lower esophagus mucosa	3
buccal mucosa cell	3
sural nerve	3
bronchial epithelial cell	2
gluteal muscle	2
hindlimb stylopod muscle	2
right hemisphere of cerebellum	2
muscle of leg	2
ventricular zone	1
liver	1
minor salivary gland	1
right lobe of liver	1
caput epididymis	1
epithelium of bronchus	1
diaphragm	1
calcaneal tendon	1
left testis	1
right testis	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CELSR1	224	ubiquitous	marker	ventricular zone, lower esophagus mucosa, bronchial epithelial cell
SERPINA11	50	tissue_specific	yes	right lobe of liver, liver, minor salivary gland
FZD6	260	ubiquitous	marker	bronchial epithelial cell, caput epididymis, epithelium of bronchus
MYBBP1A	226	ubiquitous	marker	sural nerve, buccal mucosa cell, lower esophagus mucosa
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
RYR3	233	broad	marker	diaphragm, sural nerve, right hemisphere of cerebellum
CCNH	297	ubiquitous	marker	calcaneal tendon, left testis, right testis
SLC30A5	281	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, tendon of biceps brachii
CHRNA1	149	broad	marker	gastrocnemius, gluteal muscle, muscle of leg
FLVCR2	211	ubiquitous	marker	secondary oocyte, tibial nerve, monocyte
PIEZO1	142	ubiquitous	marker	muscle layer of sigmoid colon, lower esophagus mucosa, upper lobe of left lung
SLC26A3	159	tissue_specific	marker	colonic mucosa, mucosa of sigmoid colon, rectum
MYO18A	134	ubiquitous	marker	gastrocnemius, skeletal muscle tissue, muscle of leg
HSALR1	126		yes	colonic epithelium, bone marrow cell, sural nerve
FOXP3	155	tissue_specific	marker	buccal mucosa cell, parotid gland, skeletal muscle tissue of rectus abdominis
L1CAM	239	ubiquitous	marker	cortical plate, right hemisphere of cerebellum, cerebellar hemisphere
RAPSN	159	tissue_specific	marker	hindlimb stylopod muscle, male germ line stem cell (sensu Vertebrata) in testis, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOXP3	4,306
MYBBP1A	3,719
L1CAM	2,937
PIEZO1	2,266
RYR1	2,177
CCNH	2,116
SLC30A5	1,868
SLC26A3	1,831
RYR3	1,705
FZD6	1,337

Intra-cohort edges

A	B	Sources
CELSR1	FZD6	string_interaction
CHRNA1	RAPSN	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 5 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCNH	P51946	47
CHRNA1	P02708	15
SLC26A3	P40879	13
RYR3	Q15413	10
PIEZO1	Q92508	6
FLVCR2	Q9UPI3	5
CELSR1	Q9NYQ6	2
FZD6	O60353	2
RYR1	P21817	2
FOXP3	Q9BZS1	2
L1CAM	P32004	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAPSN	Q13702	93.29
SERPINA11	Q86U17	83.27
SLC30A5	Q8TAD4	76.95
MYBBP1A	Q9BQG0	74.69
MYO18A	O95411	41.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 112. Enrichment computed across 17 evidence-associated genes (12 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC26A3 causes congenital secretory chloride diarrhea 1 (DIAR1)	1	951.7×	0.077	SLC26A3
Zinc efflux and compartmentalization by the SLC30 family	1	190.3×	0.077	SLC30A5
RUNX1 regulates transcription of genes involved in WNT signaling	1	158.6×	0.077	FOXP3
Inorganic anion exchange by SLC26 transporters	1	105.7×	0.077	SLC26A3
Signaling by RNF43 mutants	1	105.7×	0.077	FZD6
Highly calcium permeable nicotinic acetylcholine receptors	1	105.7×	0.077	CHRNA1
FGFR1 mutant receptor activation	1	95.2×	0.077	MYO18A
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	95.2×	0.077	FOXP3
FLT3 signaling in disease	1	95.2×	0.077	MYO18A
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	86.5×	0.077	CHRNA1
Ion homeostasis	2	34.0×	0.077	RYR1, RYR3
Stimuli-sensing channels	2	22.7×	0.077	RYR1, RYR3
Cardiac conduction	2	18.1×	0.077	RYR1, RYR3
Ion channel transport	2	16.0×	0.077	RYR1, RYR3
Muscle contraction	2	12.9×	0.077	RYR1, RYR3
Epigenetic regulation of gene expression	2	11.9×	0.077	CCNH, MYBBP1A
Transport of small molecules	3	6.3×	0.077	RYR1, RYR3, SLC26A3
Presynaptic nicotinic acetylcholine receptors	1	79.3×	0.078	CHRNA1
Acetylcholine binding and downstream events	1	68.0×	0.082	CHRNA1
Postsynaptic nicotinic acetylcholine receptors	1	68.0×	0.082	CHRNA1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	56.0×	0.091	PIEZO1
Signaling by cytosolic FGFR1 fusion mutants	1	52.9×	0.091	MYO18A
Signaling by FLT3 fusion proteins	1	47.6×	0.091	MYO18A
Signal transduction by L1	1	43.3×	0.091	L1CAM
Regulation of FZD by ubiquitination	1	43.3×	0.091	FZD6
Insulin processing	1	38.1×	0.091	SLC30A5
Global Genome Nucleotide Excision Repair (GG-NER)	1	38.1×	0.091	CCNH
Basigin interactions	1	36.6×	0.091	L1CAM
Signaling by FGFR in disease	1	35.2×	0.091	MYO18A
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	34.0×	0.091	CCNH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
establishment of body hair planar orientation	2	449.4×	0.001	CELSR1, FZD6
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	2	224.7×	0.003	RYR1, RYR3
cellular response to caffeine	2	204.3×	0.003	RYR1, RYR3
striated muscle contraction	2	112.3×	0.006	RYR1, RYR3
synaptic transmission, cholinergic	2	107.0×	0.006	CHRNA1, RAPSN
Wnt signaling pathway, planar cell polarity pathway	2	60.7×	0.015	CELSR1, FZD6
positive regulation of peripheral T cell tolerance induction	1	1123.5×	0.016	FOXP3
regulation of postsynaptic membrane organization	1	1123.5×	0.016	RAPSN
establishment of protein localization to postsynaptic membrane	1	1123.5×	0.016	RAPSN
CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment	1	561.7×	0.016	FOXP3
establishment of endothelial blood-brain barrier	1	561.7×	0.016	FOXP3
asymmetric Golgi ribbon formation	1	561.7×	0.016	MYO18A
positive regulation of motor neuron apoptotic process	1	561.7×	0.016	RAPSN
negative regulation of chronic inflammatory response	1	374.5×	0.016	FOXP3
transforming growth factor beta1 production	1	374.5×	0.016	FOXP3
isotype switching to IgE isotypes	1	374.5×	0.016	FOXP3
negative regulation of isotype switching to IgE isotypes	1	374.5×	0.016	FOXP3
intracellular pH elevation	1	374.5×	0.016	SLC26A3
orthogonal dichotomous subdivision of terminal units involved in lung branching morphogenesis	1	374.5×	0.016	CELSR1
planar dichotomous subdivision of terminal units involved in lung branching morphogenesis	1	374.5×	0.016	CELSR1
lateral sprouting involved in lung morphogenesis	1	374.5×	0.016	CELSR1
protein localization involved in establishment of planar polarity	1	374.5×	0.016	CELSR1
heme export	1	374.5×	0.016	FLVCR2
positive regulation of neuromuscular synaptic transmission	1	374.5×	0.016	RAPSN
zinc ion import into Golgi lumen	1	374.5×	0.016	SLC30A5
tolerance induction to self antigen	1	280.9×	0.016	FOXP3
regulation of T cell anergy	1	280.9×	0.016	FOXP3
T cell anergy	1	280.9×	0.016	FOXP3
obsolete negative regulation of CREB transcription factor activity	1	280.9×	0.016	FOXP3
establishment of planar polarity of embryonic epithelium	1	280.9×	0.016	CELSR1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 15

Druggability breadth: 11 of 17 evidence-associated genes (65%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CCNH	ABEMACICLIB
CHRNA1	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCNH	28	4
CHRNA1	12	4
CELSR1	0	0
SERPINA11	0	0
FZD6	0	0
MYBBP1A	0	0
RYR1	0	0
RYR3	0	0
SLC30A5	0	0
FLVCR2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ABEMACICLIB	4	CCNH
QUIZARTINIB	4	CCNH
ADAGRASIB	4	CCNH
VARENICLINE	4	CHRNA1
NICOTINE	4	CHRNA1
TROPISETRON	4	CHRNA1
BUPROPION	4	CHRNA1
MECAMYLAMINE	4	CHRNA1
ALVOCIDIB	3	CCNH
DINACICLIB	3	CCNH
LEROCICLIB	3	CCNH
DEXMECAMYLAMINE	3	CHRNA1
CYTISINICLINE	3	CHRNA1
SELICICLIB	2	CCNH
ASNUCICLIB	2	CCNH
CYC-065	2	CCNH
ULECACICLIB	2	CCNH
RONICICLIB	2	CCNH
AT-7519	2	CCNH
INIXACICLIB	2	CCNH
ISTISOCICLIB	2	CCNH
MILCICLIB	2	CCNH
ZOTIRACICLIB	2	CCNH
NARAZACICLIB	2	CCNH
CT-7001	2	CCNH
ZEMIRCICLIB	2	CCNH
RADAFAXINE	2	CHRNA1
GTS-21	2	CHRNA1
ALTINICLINE	2	CHRNA1
MOLIBRESIB	2	CHRNA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CCNH	348	Binding:346, Functional:2
CHRNA1	157	Binding:107, Functional:47, ADMET:2, Toxicity:1
PIEZO1	17	Binding:17
RYR1	16	Binding:13, Functional:3
SLC26A3	6	Binding:6
FOXP3	4	Binding:4
RYR3	2	Binding:2
L1CAM	2	Binding:2
MYBBP1A	1	Binding:1
SLC30A5	1	Binding:1
RAPSN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MYBBP1A	2.3.1.48	histone acetyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CCNH	348
CHRNA1	157

Pharmacogenomics

Cohort genes with a PharmGKB record: 16; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ABEMACICLIB	4	CCNH
QUIZARTINIB	4	CCNH
ADAGRASIB	4	CCNH
VARENICLINE	4	CHRNA1
NICOTINE	4	CHRNA1
TROPISETRON	4	CHRNA1
BUPROPION	4	CHRNA1
MECAMYLAMINE	4	CHRNA1
ALVOCIDIB	3	CCNH
DINACICLIB	3	CCNH
LEROCICLIB	3	CCNH
DEXMECAMYLAMINE	3	CHRNA1
CYTISINICLINE	3	CHRNA1
SELICICLIB	2	CCNH
ASNUCICLIB	2	CCNH
CYC-065	2	CCNH
ULECACICLIB	2	CCNH
RONICICLIB	2	CCNH
AT-7519	2	CCNH
INIXACICLIB	2	CCNH
ISTISOCICLIB	2	CCNH
MILCICLIB	2	CCNH
ZOTIRACICLIB	2	CCNH
NARAZACICLIB	2	CCNH
CT-7001	2	CCNH
ZEMIRCICLIB	2	CCNH
RADAFAXINE	2	CHRNA1
GTS-21	2	CHRNA1
ALTINICLINE	2	CHRNA1
MOLIBRESIB	2	CHRNA1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CCNH, CHRNA1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	7	CELSR1, FZD6, RYR1, RYR3, FLVCR2, SLC26A3, L1CAM
D	Druggable family + AlphaFold only, no drug	1	MYBBP1A
E	Difficult family or no structure, no drug	7	SERPINA11, SLC30A5, PIEZO1, MYO18A, HSALR1, FOXP3, RAPSN

Undrugged target profiles

15 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CELSR1	0	—
SERPINA11	0	—
FZD6	0	—
MYBBP1A	1	—
RYR1	16	—
RYR3	2	—
SLC30A5	1	—
FLVCR2	0	—
PIEZO1	17	—
SLC26A3	6	—
MYO18A	0	—
HSALR1	0	—
FOXP3	4	—
L1CAM	2	—
RAPSN	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02986698	PHASE1	TERMINATED	In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)
NCT03412760	Not specified	ACTIVE_NOT_RECRUITING	Hydrops: Diagnosing & Redefining Outcomes With Precision Study
NCT03775954	Not specified	RECRUITING	Fetal Electrophysiologic Abnormalities in High-Risk Pregnancies Associated With Fetal Demise
NCT00143039	Not specified	TERMINATED	Amniotic Fluid Tandem Mass Spectrometry for Pregnancies Complicated by NIH and Severe Symmetrical IUGR
NCT02956564	Not specified	UNKNOWN	Precision Medical Research of Non-immune Fetal Hydrops (NIFH)-From Prenatal Diagnosis to Intrauterine Treatment
NCT03376438	Not specified	COMPLETED	Prospective Observational Cohort Study of Fetal Atrial Flutter & Supraventricular Tachycardia

Cohort genes: CELSR1, SERPINA11, FZD6, MYBBP1A, RYR1, RYR3, CCNH, SLC30A5, CHRNA1, FLVCR2, PIEZO1, SLC26A3, MYO18A, HSALR1, FOXP3, L1CAM, RAPSN